The recurrence of pulmonary metastases that are resistant to salvage chemotherapy regimens continues to be a major problem in children with osteosarcoma (OS). Recurrence rates following thoracic surgery to remove all visible metastases have continued to hover around 80% at I year regardless of the salvage chemotherapy employed. Now agents and novel combinations involving different kinds of therapy are needed if this "progression-free survival" is to be improved. A phase Il study will determine the efficacy of combining IL-1alpha with etoposide in relapsed OS. Preclinical data demonstrated that IL-1alpha dramatically increased the sensitivity of OS cells to etoposide when given simultaneously in vitro. This increase in sensitivity was not seen when etoposide treatment preceded IL-I treatment. Relapsed OS patients with measurable disease will be eligible. IL-1alpha will be administered subcutaneously followed by i.v. etoposide. Combination therapy will be given for 5 days every 3 weeks for 9 cycles. Tumor response will be assessed after 3 cycles. Patients with resectable pulmonary metastases will undergo surgery to assess histologic response. Those with stable disease or response will receive up to 6 cycles postoperatively. Patients with unrespectable disease will be restaged after 3 cycles and in the absence of progressive disease, can receive 6 more cycles. Preclinical data demonstrated that IL-1alpha increased etoposide-induced DNA cleavage and the expression of topoisomerase II (topo II) suggesting that topo II was involved in the enhanced cytotoxic activity seen. We will quantify cellular topo II and the topo II-DNA complexes in patients' mononuclear cells before and after therapy. Blood levels of IL-1alpha and etoposide will be monitored. We will assess the plasma pharmacokinetics of etoposide as well. An additional goal is to determine if tumor response can be correlated with the in vivo production of topo II-DNA complexes and blood levels of etoposide.